This is the second competing renewal application of the Vanderbilt-lngram Cancer Center (VICC) Breast Cancer SPORE Grant. We have made significant progress in our previous funding cycle, have established productive collaborations with other Breast Cancer SPOREs and national and international groups, and have firmly established a true multidisciplinary program which we believe will be increasingly productive in the years to come. Our overall goal continues to be to conduct multidisciplinary, mechanism-based, translational research of the highest possible impact that will contribute meaningfully to measurable progress in breast cancer. To this end and after internal and external review, we now propose four bidirectional translational projects addressing basic, clinical and population research questions in human breast cancer. Two of these are continuations and two are new projects. The application also includes five shared cores resources, and developmental research and career development programs. Project 1: Inhibition of PI3 kinase as a strategy to abrogate antiestrogen resistance in breast cancer Project 2: Strategies to improve outcomes for triple negative breast cancer patients involving subtype-specific targeted therapies and genomic discovery Project 3: Mcl-1 inhibitors for the treatment of breast cancer Project 4: The obesity-metabolic biomarker axis and breast cancer risk Core Resources. To support the research aims in the translational research projects, we propose five shared Core Resources. Each of these Cores supports at least 2 projects in this competing renewal. They are Administration & Outreach, Pathology & Tissue Informatics (formerly called Tissue), Clinical, Biostatistics, and Imaging Cores. We should emphasize that these Cores do not duplicate pre-existing resources available at VICC or VUMC. The proposed Projects will require additional personnel and funded effort over that already maximally utilized in equivalent institutional Core Resources.